Third Trimester Placenta

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2018, Case 05, and is chorangioma of the placenta.

Microscopic evaluation of the lesion reveals a proliferation of capillaries lined by mostly plump endothelial cells associated with scattered larger caliber blood vessels. In some areas vascular congestion is prominent. Other findings include areas of necrosis, hyalinization, calcification, and hemorrhage. Patchy acute inflammation is present, mostly in association with the necrotic areas. Some larger caliber vessels exhibit various stages of luminal thrombi formation. In a few foci, the surface of the lesion is covered by a mild non-atypical syncytiotrophoblastic proliferation. Some of the adjacent chorionic villi are necrotic. The histological findings are consistent with a diagnosis of chorangioma with focal degenerative changes.

Chorangioma (CA) is the most common primary placental tumor. The incidence of this benign tumor varies from 1 in 9,000 to 1 in 50,000 placentas, although according to some authors it may be as high as one in 100 placentas (considering that many CA are small and may be missed during gross placental evaluation). CA are more commonly identified between 32 and 37 weeks of gestation, in placentas of female fetuses, in primigravidas, and in Caucasian patients. The incidence is also increased in several settings, including preeclampsia, multiple gestations, newborns with congenital anomalies (in particular those with hemangiomas), pregnancies with elevated nucleated red blood cells in the fetal circulation, and in patients living in high altitudes.

Some authors describe CA as true neoplasms, while others refer to them as either congenital malformations or hamartomas. Recent studies suggest that they arise from stem chorionic villi. Although their true nature is still debated in the literature, a well-documented association between the high frequency of CA in populations delivering at high elevations as well as their presence in pregnancies complicated by maternal hypoxemia (eg, preeclampsia, maternal diabetes mellitus) strongly suggests that hypoxia-related vascular proliferative changes likely play a role in their development. Also, according to the literature, chorangiomatosis and chorangiosis (2 entities in the differential diagnosis of CAs) likely represent an adaptive response to hypoxic-ischemic placental events.

Maternal, fetal, and neonatal complications associated with CAs include hydrops fetalis, polyhydramnios, preterm labor, disseminated intravascular coagulation, fetal hemolytic anemia, fetal thrombocytopenia, fetal myocardial dysfunction, intrauterine growth restriction, placental abruption, preterm labor, and intrauterine fetal demise. Numerous articles identify lesional size (greater than 4.0 cm) as the main factor associated with these complications, highlighting (for example) the negative effect of large CAs in the feto-placental circulation. However, the pathophysiology of the majority of these complications is not well understood and some authors warn that size alone may not be the only factor, as multiple smaller CAs (or even chorangiosis) can be associated with similar adverse clinical outcomes. Most CAs are small, single, and asymptomatic incidental findings, and it is estimated that less than 10% of them are greater than 4.0 cm in greatest dimension. Although the presence of multiple CAs is an infrequent finding, familial recurrences of multiple CAs in subsequent pregnancies have been reported in the literature.

CA may be single or multiple and are commonly noted in the subchorionic or marginal aspects of the placenta (sites known to have reduced oxygenation). They are well-circumscribed lesions, and those with a subchorionic location tend to bulge from the fetal surface. CA vary from red and soft to firm and white; the color and consistency of the cut surface is variable, and reflects focal or diffuse degenerative changes like infarction, calcification, and fibrosis. Microscopically, CA are characterized by a proliferation of capillary or sinusoidal fetal blood vessels associated with variably dense connective tissue stroma. They may be separated into various subtypes (capillary, cavernous, endotheliomatous, fibrosing, and fibrous) based on the amount of stroma present at the time of evaluation, but these subtypes are of no clinical significance. Ancillary studies (eg, immunohistochemical stains) are usually not necessary to confirm the diagnosis of a CA but, if needed, vascular markers (eg, CD31, CD34) can be of assistance. Rare benign lesions may exhibit increased cellularity, cytologic atypia, and significant mitotic activity. Other unusual findings include the presence of Wharton jelly in CA arising adjacent to the base of the umbilical cord (resulting in myxoid features) and the presence of significant intratumoral smooth muscle. It is not unusual for CAs to be covered by trophoblasts that occasionally can exhibit a significant degree of hyperplasia. Many authors believe that rare tumors described in the literature as “chorangiocarcinomas” likely represent CAs with prominent surface trophoblastic proliferations. However, rare reported cases demonstrating a malignant trophoblastic proliferation in association with a chorangioma exist in the literature. Although some cases may represent a “collision tumor” resulting from a chorangioma arising in close proximity with an intraplacental choriocarcinoma, it is advisable to be cautious when evaluating a chorangioma with a significant and/or atypical trophoblastic proliferation.

The microscopic differential diagnosis of a CA includes chorangiomatosis (localized and diffuse multifocal), and chorangiosis. Chorangiomatosis is an increase in the number of villous capillaries that tends to permeate the normal villous structures and involves immature intermediate or stem chorionic villi (sparing terminal and tertiary stem villi); its clinical significance is unknown at this time. The vessels in chorangiomatosis are bordered by loosely arranged reticular fibers that merge with the villous stroma. Chorangiomatosis also shares histological features with CA, including the presence of perivascular cells (pericytes) and increased stromal cellularity and collagen deposition. The localized pattern of chorangiomatosis can be focal or segmental and tends to be found in the subchorionic aspect of the placenta and at the margin of the disc. The focal pattern involves less than or equal to 5 contiguous villi, while the segmental pattern involves greater than 5 contiguous villi. Localized chorangiomatosis can be seen in association with preeclampsia, premature birth, and multiple gestations. The diffuse multifocal pattern affects secondary and tertiary stem villi throughout the placenta and, occasionally, may be grossly identified as multiple placental parenchymal nodules. This pattern can be associated with preeclampsia, premature delivery, intrauterine growth restriction, large placentas, and congenital anomalies.

Chorangiosis (also known as hypercapillarization) is limited to distal villi (terminal villi and the margins of tertiary stem villi) and has been defined as “ten or more capillaries in each of ten villi in ten fields inspected with a 10x objective in three different, noninfarcted areas of the placenta.” The capillaries in chorangiosis are only surrounded by a thin basement membrane and lack perivascular cells (pericytes). Chorangiosis can be identified in close to 7% of placentas, the majority of them at term and usually large for gestational age. Chorangiosis can be seen in association with maternal diabetes mellitus, preeclampsia, severe maternal anemia, and fetal overgrowth syndromes (Beckwith-Wiedemann and Smith-Golabi-Behmel); it has not been determined to be an independent risk factor for adverse pregnancy-related outcomes.

The antenatal differential diagnosis of a placental tumor following medical imaging studies (ultrasonography, color Doppler, magnetic resonance imaging) includes CA, teratoma, hematoma, partial hydatidiform mole, leiomyoma, and metastases. In this setting, follow-up of a placental tumor allows for the development of a treatment approach to prevent (or at least reduce) obstetrical complications. Small tumors are monitored by ultrasonography every 6 to 8 weeks while large tumors are monitored every 1 to 2 weeks. When antenatal treatment needs to be instituted to limit or end the effect of the CA, several options are available, including laser coagulation of the vessels supplying the tumor, chemical sclerosis with absolute alcohol, and endoscopic surgical devascularization. Other treatment modalities (amnioreduction, fetal intrauterine blood transfusion) can also assist in reducing the negative effects of a CA on the health of the mother and/or the fetus.

1. Which of the following pregnancy-related complications are associated with chorangiomas?
   
   
   1. Disseminated intravascular coagulation, fetal hemolytic anemia, and fetal thrombocytopenia
   2. Fetal overgrowth syndromes (Beckwith-Wiedemann and Smith-Golabi-Behmel)
   3. Maternal infertility, recurrent miscarriages, and maternal autoimmune diseases
   4. Necrotizing umbilical periphlebitis, true umbilical cord knots, and diffuse umbilical cord edema
   5. Placenta accreta resulting in hysterectomy
2. Which of the following defines chorangiosis?
   
   
   1. An increase in the number of villous capillaries that tends to permeate the normal villous structures and involves immature intermediate or stem chorionic villi (sparing terminal and tertiary stem villi)
   2. Numerous capillaries in each of 10 villi in ten fields inspected with a 10x objective in 3 different, noninfarcted areas of the placenta
   3. Ten or more capillaries in each of 10 villi in ten fields inspected with a 10x objective in 3 different, noninfarcted areas of the placenta
   4. Ten or more capillaries in each of 10 villi in ten fields inspected with a 20x objective in 3 different, noninfarcted areas of the placenta
   5. Twenty or more capillaries in each of 10 villi in ten fields inspected with a 10x objective in 3 different, noninfarcted areas of the placenta
3. Which of the following is true of chorangiomas?
   
   
   1. Microscopic lesions that increase the chances of placental abruption
   2. Most are greater than 4.0 cm in greatest dimension
   3. Multifocal small lesions that bleed profusely during the third trimester of pregnancy
   4. Small, multiple, and painful lesions that require maternal bedrest
   5. Small, single, and asymptomatic incidental findings

1. Ariel I, Boldes R, Weintraub A, Reinus C, Beller U, Arbel R. Chorangiocarcinoma: a case report and review of the literature. Int J Gynecol Pathol 2009;28(3):267-271.
2. Baergen RN. Chapter 19, Miscellaneous placental lesions. In: Baergen RN, ed. Manual of Pathology of the Human Placenta. 2nd ed. New York, NY; Springer Science+Business Media, Inc; 2011:362-366.
3. Baergen RN. Chapter 22, Neoplasms. In: Baergen RN, ed. Manual of Pathology of the Human Placenta. 2nd ed. New York, NY; Springer Science+Business Media, Inc; 2011:415-421.
4. Benirschke K, Burton GJ, Baergen RN. Chapter 24, Benign tumors and chorangiosis. In: Pathology of the Human Placenta 6th ed. Berlin, Heidelberg. Springer-Verlag; 2012:747-755.
5. Kirkpatrick AD, Podberesky DJ, Gray AE, McDermott JH. Best cases from the AFIP: Placental chorioangioma. Radiographics. 2007;27(4):1187-1190.
6. Kraus FT, Redline RW, Gersell DJ, Nelson DM, Dicke JM. Chapter 5: Inflammation and infection. In: Placental Pathology (Atlas of Nontumor Pathology) 1st Series, Fascicle 3. Washington DC. American Registry of Pathology in collaboration with the Armed Forces Institute of Pathology. 2004:61-65.
7. Miliaras D1, Anagnostou E, Papoulidis I, Miliara X. Non-trophoblastic tumor of the placenta with combined histologic features of chorangioma and leiomyoma. Placenta. 2011;32(1):102-104.
8. Sirotkina M, Douroudis K, Westgren M, Papadogiannakis N. Association of chorangiomas to hypoxia-related placental changes in singleton and multiple pregnancy placentas. Placenta. 2016;39:154-159.

Nilsa C. Ramirez, MD, FCAP
Surgical Pathology Committee
Nationwide Children’s Hospital
Columbus, OH

1. Disseminated intravascular coagulation, fetal hemolytic anemia, and fetal thrombocytopenia (a)
2. Ten or more capillaries in each of 10 villi in ten fields inspected with a 10x objective in 3 different, noninfarcted areas of the placenta (c)
3. Small, single, and asymptomatic incidental findings (e)